PhD Candidate Ragon Inst. of MGH, MIT, and Harvard Setauket- East Setauket, New York, United States
Disclosure(s):
Kirti Nath, BS, BA: No financial relationships to disclose
Introduction/Rationale: The endometrium undergoes a coordinated and cyclic turnover that is unlike any other mammalian tissue. In mice, this process entails a 20-40% reduction in endometrial cellularity over a 12–24-hour time frame. This remarkable coordination raises fundamental questions about how such rapid and synchronized cell death is achieved across distinct cell types. Notably, the healthy, non-pregnant endometrium, in both mice and humans, harbors diverse immune cells that, in principle, could mediate or facilitate endometrial breakdown. T cells stand out as compelling candidates due to their ability to recognize and respond to tissue-restricted antigens. Therefore, we hypothesized that T cells specific for endometrial antigens act as physiological mediators of tissue breakdown, coordinating the timing and extent of endometrial cell death.
Methods: We integrated 3D volumetric imaging of optically cleared uteri with targeted genetic perturbations, temporally resolved manipulations across the estrous cycle, and adoptive transfer of defined T cell populations.
Results: We found that a population of conventional CD4⁺ T cells dynamically traffics from uterus-draining lymph nodes to the endometrium at defined stages of the estrous cycle, where they become locally activated in a TCR-dependent manner. Depletion of commensal microbes did not alter their activation or accumulation, indicating that these responses are most likely driven by self-antigens. Genetic ablation or acute depletion of CD4⁺ T cells markedly delayed endometrial degradation and disrupted the synchrony of epithelial and stromal cell death.
Conclusion: Our data identify a controlled autoimmune T cell response as a physiological mechanism that orchestrates the cyclical breakdown of the endometrium. These findings challenge the view of autoimmunity as exclusively pathological and position self-reactivity as an essential component of homeostasis, with broad implications for understanding immune regulation, tissue remodeling, and reproductive health.
